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Treatment of hepatitis B viral (HBV) infection depends on how active the virus is and whether you are at risk for liver damage such as cirrhosis.
The goals of HCV treatment are to remove the virus from the blood and reduce the risk of cirrhosis and liver cancer that can result from long-term HCV infection.
Many of the medicines used to treat hepatitis B are not helpful for treating hepatitis D (See hepatitis B). Science, Technology and Medicine open access publisher.Publish, read and share novel research.
Current Concepts on Management of Chronic Hepatitis BTeresa Santantonio1 and Massimo Fasano1[1] Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy1. D Lavanchy, Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. A Zerbini, M Pilli, C Boni, P Fisicaro, A Penna, P Di Vincenzo, et alThe characteristics of the cell-mediated immune response identify different profiles of occult hepatitis B virus infection.
G Fattovich, F Bortolotti, F Donato, Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. X Wu, Z Xin, X Zhu, L Pan, Z Li, H Li, et alEvaluation of susceptibility locus for response to interferon-alpha based therapy in chronic hepatitis B patients in Chinese. Hepatitis B is an incurable infection, so the best hepatitis B treatment is preventing it altogether. The first drugs approved in the United States for chronic hepatitis B treatment were alpha-interferons.
Along with injected interferon medications, there are a number of oral medications approved for treating chronic hepatitis B infections.
The chance of a hepatitis B infection leading to liver disease is relatively small, although still a possibility.
Home treatment will usually help relieve your symptoms and help you prevent the spread of hepatitis A virus (HAV). If you believe you have recently been exposed to HBV, you should receive a shot of hepatitis B immune globulin (HBIG) and the first of three immunization shots of hepatitis B vaccine.
Persons with long-term HDV infection may receive a medicine called alpha interferon for up to 12 months. However, several studies for the development of an effective vaccine against hepatitis E are in progress.
IntroductionAn estimated 400 million people are chronically infected with hepatitis B virus (HBV), worldwide, and over 500,000 chronic hepatitis B (CHB) patients die annually because of cirrhosis and hepatocellular carcinoma (HCC) [1,2]. R Brunetto, F Oliveri, P Colombatto, F Moriconi, P Ciccorossi, B Coco, et alHepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers.
Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. K Lau, F Bonino, et alPeginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
R Piras, G Antonucci, et alA randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B.
A randomized trial of peginterferon alpha-2a with or without ribavirin for HBeAg-negative chronic hepatitis B. Randomised study comparison 48 and 96 weeks peginterferon ?-2a therapy in genotype D HBeAg-negative chronic hepatitis B. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomized trial. The hepatitis B vaccine is safe for most people and recommended for all infants and children under the age of 19. Interferon is naturally produced by the body to fight against invading viruses and other organisms.
The first oral medication approved for use was lamivudine (Epivir-HBV, Zeffix, or Heptodin), a pill taken once per day for a year or longer.
According to the Centers for Disease Control and Prevention, HBsAg, the antigen that indicates an HBV infection, will show up in an infected persons blood on an average of four weeks after exposure to the virus. The most common medications are a combination of pegylated interferon alfa and ribavirin, an antiviral medication. Hepatitis E is a viral disease, and as such, antibiotics are of no value in the treatment of the infection.
Clinical care for patients with CHB has advanced considerably during the last decades as a result of growing knowledge about the mechanisms of disease, diagnostic procedures and advances in therapeutic options. This goal can be achieved if HBV replication can be suppressed in a sustained manner, thus leading to biochemical remission, HBe seroconversion in HBeAg-positive patients, histological improvement and prevention of cirrhosis and its complications. First-line monotherapyPeg-IFN, entecavir or tenofovir are recommended as first-line monotherapy by all major guidelines in patients with CHB or compensated cirrhosis [7-9]. Summary and conclusionsChronic hepatitis B remains a serious clinical problem because of its worldwide distribution and potential progression of liver damage.
S Akarca, et alThe safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. X Luo, P Marcellin, S Thongsawat, G Cooksley, et alPeginterferon alpha-2a, Lamivudine, and the combination for HBeAg-positive chronic hepatitis B. M Lu, Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. The vaccine can even be effective after exposure to the hepatitis B virus (HBV), if administered promptly.
Taking additional artificially-produced interferon can help stimulate the bodys immune response and help stop HBV from replicating.
First approved by the FDA in 1998, this antiviral medication, a nucleoside analogue, can be as effective as interferon-alpha for reducing the serum HBeAg in blood and helps prevent HBV from replication.
About half of all affected patients are no longer infectious seven weeks after the symptoms appear, and all patients who do not remain chronically infected will test negative for HBsAg by 15 weeks after symptoms show up. People with hepatitis C should also be careful not to take vitamins, nutritional supplements, or new over the counter medications without first discussing it with their health care provider. Since the introduction of interferon alpha as first antiviral therapy at the end of the 1980s, management of CHB has dramatically evolved due to the availability of direct antivirals which greatly increased the therapeutic options, thus permitting treatment of patients previously excluded from IFN treatment. Several studies have demonstrated that undetectable or low levels of HBV DNA are associated with a lower risk to develop cirrhosis [12-14]. The choice of first-line monotherapy should be based on several factors including host, virus and drug related factors (Figure 5).
Over the last decades, treatment of CHB has greatly advanced due to the availability of safe and effective drugs and guidelines have been developed. H Han, et alAsian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. According to the Mayo Clinic, a hepatitis B immune globulin injection within 24 hours of exposure may protect against developing hepatitis B.
Those patients that do remain chronically infected and do not seek treatment are at greater risk of serious complications such as cirrhosis and liver cancer. Adults who are at high risk for hepatitis B infection, and all children should consider getting this vaccine. In particular, new oral antivirals have been developed and used in clinical practice, leading to a substantial improvement in antiviral efficacy, mainly due to their increased potency and higher barrier to resistance. Loss of HBsAg from serum with or without seroconversion to anti-HBs is considered the ideal end-point of therapy, as it is associated with remission of chronic hepatitis B activity and an improved long-term outcome [11]. The most favourable candidates for Peg-IFN are those with low HBV DNA levels, high ALT and HBV genotype A or B rather than C or D, and those without advanced disease. Both Peg-IFN and two NAs, entecavir and tenofovir, can currently be indicated as first-line therapies for CHB. W Leung, L Lu, et alNatural History and Disease Progression in Chinese Chronic Hepatitis B Patients in Immune-tolerant Phase. S Chen, M Colombo, et alStatements from the Taormina expert meeting on occult hepatitis B virus infection. E Hansen, H Janssen, Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B. L Janssen, Prediction of sustained response to peginterferon alpha-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline.
Exposed individuals should also immediately start the series of three injections of the vaccine. These conditions can eventually lead to liver failure, which may require a liver transplant for survival.
Don’t go to work or school unless your workload can be reduced to match your energy level. You need also avoid alcohol and drugs but you have to drink plenty of liquids to avoid dehydration.
On the other hand, the expanding molecular and clinical knowledge of HBV infection and evolution of therapy have made the management of CHB patients much more complex. The loss of HBsAg, however, is infrequently achieved with currently available anti-HBV agents. Peg-IFN alpha-2a is administered as subcutaneous injections at the dose of 180 ?g once weekly for 48 weeks. Peg-IFN treatment is a short-term treatment strategy which provides a significant off-treatment sustained responses, including loss of HBsAg. J Chen, et alPredicting cirrhosis risk based on the level of circulating hepatitis B viral load. N Lu, et alRisk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. L Chuang, et alShorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C. Try to control itching and prevent the spread of HBV by informing people you live with or sleep  with about the illness, by not sharing personal toiletries (such as razors and toothbrushes), and by using a condom or abstaining from sex.


As no specific therapy is capable of altering the course of acute hepatitis E infection, prevention is the most effective approach against the disease. Hence, a more realistic end-point is the induction of a sustained or maintained virological response.
Entecavir or tenofovir are the only therapeutic options in patients with decompensated liver disease, in patients undergoing immunosuppressive treatment, in patients with controindications or unwilling to receive Peg-IFN.
However, as Peg-IFN is effective in 20-30% of patients, it should, therefore, be considered only for patients with an elevated possibility of response based on pre-treatment and on-treatment factors. S Hsu, et alEffect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon alpha-2a therapy. If chronic hepatitis B develops, there are few treatment options, but there are a number drug therapies used to care for the infection. Evidence of an ongoing inflammation of the liver should also be demonstrated, and a liver biopsy is usually performed before treatment is administered. It might also instigate a drug-resistant form of HBV, especially when used for extended periods of time. Hospitalization is required for fulminant hepatitis and should be considered for infected pregnant women. Pre-therapeutic assessmentChronic HBV infection is not necessarily accompanied by progressive liver disease requiring antiviral therapy.
The licensed entecavir dose for patients with decompensated cirrhosis is 1 mg (instead of 0.5 mg for patients with CHB or compensated liver disease) once daily.
In particular quantitative HBV-DNA and HBsAg may be suitable to early identify patients who are unlikely to benefit from Peg-IFN early during the treatment course, thereby avoiding unnecessary treatment. Most adults infected with HBV do recover fully, even if they exhibit severe symptoms, but infants and children who contract the virus are much more apt to acquire a chronic infection. In addition, patients with severe liver diseases, extremely high serum bilirubin and encephalopathy should not be treated unless as part of an approved clinical study.Two interferon medications, interferon alfa-2b (Intron A) and peginterferon alfa-2a (Pegasys), are available.
Adevofir dipivoxil (Hepsera), another nucleoside analogue, was approved for adult use in 2002. Therefore, as a first step, an accurate evaluation of all HBsAg-positive carriers is required in order to identify: a) the phase of infection, b) the subjects with chronic liver damage, c) the stage of liver disease, d) the concurrent causes of liver disease, and e) patients requiring treatment. Nevertheless, despite this individualised and response-guided approach, increasing the cost-effectiveness of Peg-IFN therapy remains a clinical challenge.
Intron A has been available since 1991 and is approved for both adults and children with chronic infections.
The natural history of chronic HBV infection can be divided into five, not necessarily sequential, phases (Figure 1).
Currently, IFN has been replaced by Peg-IFN due to the more convenient administration (once weekly).
Combining Peg-IFN with NA appears to be the most appealing approach to increase the efficacy of antiviral therapy and new trials on a combination of Peg-IFN with ETV or TDF are required.Currently, nucleos(t)ides analogues represent the treatment option used in the majority of CHB patients due to their potent antiviral effect, oral administration (one oral tablet daily) and optimum tolerance.
Like lamivudine, Hespera prevents HBV from replicating and has limited side effects, although symptoms may get worse after treatment has ended.
If you believe you may be experiencing a medical emergency, then call for emergency medical help. Firstly, the (i) immune-tolerant phase is characterized by high levels of serum HBV DNA, HBeAg positivity, normal ALT levels, and mild or absent liver necroinflammation. There are two pegylated-IFN formulations: Peg-IFN alpha-2a and Peg-IFN alpha-2b which have shown similar efficacy in clinical trials, but only the former is globally licensed for treatment of CHB, while Peg-IFN alpha-2b has been approved in only a few countries. In registration trials, entecavir and tenofovir, third-generation potent antivirals with a high barrier to resistance, showed long-term HBV-DNA suppression, low rise of resistance, potential reversion of fibrosis and no progression to cirrhosis, and lower risk of adverse clinical events in cirrhotic patients, except for HCC development.
Hespera has been shown to be effective against HIV but can cause kidney problems in some patients. It is very important to keep your body well-hydrated when you have hepatitis A, especially if you have vomiting.
Virological and non-virological monitoringDuring Peg-IFN therapy, full blood counts and serum ALT levels should be monitored monthly and TSH should be assessed every 3 months.
Real life studies have confirmed the long-term efficacy and safety of these two first-line NAs. After a variable time depending on the age at acquisition of HBV infection, immune-tolerance to the virus is lost and the immune system mounts an attack on the infected hepatocytes, thus entering into the (ii) immune-reactive phase.This phase is characterized by ?uctuating, but progressively decreasing, HBV-DNA levels, elevated ALT and hepatic necroin?ammation (HBeAg-positive CHB). Peg-interferonPeg-IFN is a cytochine with a dual antiviral and immunomodulatory activity and is administered by subcutaneous injections.
However, NAs require a long-term, perhaps indefinite, treatment thus raising several concerns: patient’s commitment to lifelong treatment, adherence, long-term safety, drug resistance in the long-term and costs. A prolonged immune-reactive phase with multiple ALT flares may result in progressive liver fibrosis, leading to cirrhosis. After binding with receptors located on the surface of several different cells, it induces the activation of at least 40 cellular genes, encoding for several antiviral proteins. Serum HBV DNA levels should be assessed by real-time PCR at 3, 6, 12 months during treatment and at 6 and 12 months post-treatment.
Combination of IFN and NAs might achieve an antiviral synergy and provide new opportunities to increase HBsAg clearance rates and shorten treatment duration. This antiviral medication is taken in pill form once per day for a year or longer, and causes limited side effects.
Peg-IFN suppresses HBV virion budding, HBV entry and synthesis of the nucleocapsid; moreover, this cytochine enhances the interaction between the antigen-presenting cells and CD4, and between CD8 and infected hepatocytes. Quantitative determination of serum HBsAg levels should be checked after 3 months of therapy in order to identify patients with a low probability of response in whom IFN therapy discontinuation should be considered [7]. Studies that have compared Baraclude with lamivudine have shown Baraclude to be more effective. If you take drugs (legal or illegal) or drink alcohol when you have hepatitis, their effects may be more powerful and may last longer. The estimated annual incidence of spontaneous HBeAg seroconversion is 2%-15%, depending on factors such as age, ALT levels, and HBV genotype [2]. Therefore, Peg-IFN has the potential for an immune-mediated control of HBV infection, thus providing the opportunity to obtain a sustained virological response after treatment discontinuation, and the possibility of inducing HBsAg loss in patients who achieve and maintain undetectable HBV DNA. In a minority of patients, despite HBe seroconversion, reactivation of HBV replication may occur due to the selection of HBeAg defective HBV mutants.
IFN-based treatment, however, is often complicated by the occurrence of side effects, such as influenza-like symptoms, fatigue, neutropenia, thrombocytopenia, and depression, which sometimes require dose modification and cause premature cessation of treatment [15]. Lastly, in all responder patients, HBsAg should be checked at 12-month intervals [7].In patients treated with NAs, HBV DNA levels should be monitored at month-3 to ascertain virological response, and thereafter, every 3-6 months.
Telbivudine (Tyzeka) is an antiviral medication approved for adult use in 2006 that is similar to lamivudine but slightly stronger. This (iv) reactivation phase is characterized by positivity for anti-HBe antibodies, fluctuating HBV DNA and ALT levels and a high risk of progression to severe hepatic fibrosis (HBeAg-negative CHB). Moreover, Peg-IFN is contraindicated in patients with decompensated HBV-related cirrhosis or autoimmune disease, in patients with uncontrolled severe depression or psychosis, in patients receiving immunosuppressive therapy or chemotherapy, and in female patients during pregnancy [7].7. In patients treated with ETV or TDF, the frequency of DNA measurements may be decreased once patient compliance and treatment efficacy are confirmed. Studies have shown Tyzeka to be more effective than other common treatments like lamivudine and Hepsera, but like lamivudine it can cause a drug-resistant form of HBV, especially when taken over a long period of time.
You can use nonprescription medicines, such as Benadryl or Chlor-Trimeton, to control the itching. Therefore, to warrant an accurate differential diagnosis, it is mandatory to monitor serum HBV-DNA by sensitive and quantitative polymerase chain reaction (PCR) assays and ALT levels over a period of at least 1 year.
As a result, NAs block the production of new virions and progressively reduce serum HBV DNA to undetectable levels, but they have little or no effect on the cccDNA present in the nucleous of the infected hepatocytes. HBsAg should be checked at intervals of 12 months in all patients with undetectable HBV DNA by real-time PCR [7].All NAs are cleared by the kidneys, therefore all patients should be tested for serum creatinine levels and estimated creatinine clearance at baseline to identify the need for dose adjustments. The persistence of the intrahepatic cccDNA determines the reactivation of HBV replication after stopping NA treatment and therefore justifies the need for a long-term (potentially life-long) therapy for a sustained viral replication control.After lamivudine (LAM), the first nucleoside analogue approved for the treatment of CHB, another two nucleosides, telbivudine (LdT) and entecavir (ETV), and two nucleotide analogues, adefovir (ADV) and tenofovir (TDF) have become gradually available in recent years. As the nephrotoxic potential damage seems to be higher for nucleotide analogues, it is recommended for patients treated with ADV or TDF renal monitoring, including serum phosphate levels every three months during the first year and every 6 months thereafter. Tenofovir (Viread) is another drug, approved by the FDA for adult use in 2008, which is taken in pill form once a day for a year or longer. In the (V) “HBsAg-negative phase” after HBsAg loss, low-level HBV replication may persist with detectable HBV DNA in the liver [5]. Entecavir and tenofovir are the two most potent analogues with a high barrier to resistance development.
In both tolerant and inactive HBV carriers, treatment is not indicated, but an appropriate longitudinal follow-up is crucial. Immunotolerant patients should be subjected to ALT measurements every 3-6 months and should be tested for the presence of HBeAg every 6 months. In a registration trial, Peg-IFN alpha-2a provided a sustained immune control which increased post-therapy; in fact, the HBeAg seroconversion rate continued to increase from 27% at the end of treatment to 32% during the six months after discontinuing treatment, and to 42% after 1 year post-treatment [16,17].
In the inactive carriers, ALT and HBV DNA levels should be assessed every 3 months during the first year, and then every 6 months [7-9]. The first strategy aims to obtain a sustained suppression of viral replication off-treatment by inducing an immune controll status of HBV infection. Moreover, the seroconversion remained stable over time in >80% of Peg-IFN alpha-2b treated patients achieving this end-point at the end of therapy [18].
A liver biopsy would be useful for determining the grade of necroinflammation and stage of fibrosis.
This strategy is IFN-based (Peg-IFN administered for 48 weeks); a finite treatment with NA is possible only in HBeAg-positive patients. Among these, 88% maintained this response up to 5-year follow-up, and remarkably 28% achieved HBsAg clearance after 5-years post-treatment [20].Thus, Peg-IFN treatment remains an attractive therapeutic option, since it provides higher rates of off-therapy immune control, including HBsAg clearance, when compared with NAs. Prognosis and management of CHB greatly depend on the stage and progression of liver fibrosis and thus the risk of developing cirrhosis.


However, IFN is effective in only a minority of patients (20-30%), has a poor tolerability and significant costs. In addition, liver biopsy may help to clarify diagnosis when ALT and HBV DNA levels are discordant and to exclude other coexistent causes of liver disease (e.g. Several attempts have been made to optimize the cost-effectiveness of IFN-based therapy, including combination therapy, duration of therapy, pre-treatment predictors of response, and on-treatment predictors of response. However, liver biopsy is an invasive procedure which can be painful, and carries a small risk of complications; it is also costly and prone to sampling errors. De novo combination therapy with NAs, did not improve sustained response in either HBeAg-positive or HBeAg-negative patients [16,21-23]. Regarding duration of therapy, the NEPTUNE study conducted in patients with HBeAg-positive CHB reported that dose and duration are important because the highest sustained response was obtained with 180 µg and 48 weeks compared to 90 µg and 24 weeks [24]. Recently, non-invasive methods, including serum markers and transient elastography, are being increasingly utilized to assess liver fibrosis [10].
A recent study has demonstrated that extended treatment with Peg-IFN alpha-2a to 96 weeks was well-tolerated and improved the rates of sustained virological response (29% vs 12%) in HBeAg-negative genotype D patients when compared to the current standard of care of 48 weeks. Transient elastography (FibroScan) is a rapid, noninvasive, and reproducible method for measuring liver stiffness, which correlates with the degree of liver fibrosis.
In addition, after 1-year post-treatment, HBsAg clearance (6%) was observed only in the extended therapy group [25]. It has demonstrated a high diagnostic accuracy for the detection of cirrhosis, but transient elastography might be inaccurate in discriminating between the different stages of intermediate fibrosis (F1 vs F2), F2 being considered the threshold for initiating antiviral therapy. There have been many attempts to identify pretreatment predictors of response, resulting in the identification of high ALT levels, low HBV DNA, and virus genotype as significant predictors [7-9]. Moreover, stiffness measurement may be influenced by potential confounding factors such as additional space-occupying tissue abnormalities (e.g. When combining data from the two largest clinical trials regarding HBeAg-positive CHB patients [16,26], Buster et al. Treatment indicationsCandidates for treatment are the HBsAg carriers with CHB and, consequently, those with active viral replication, increased ALT levels and evidence of liver disease at liver biopsy or other non-invasive methods.
The comparison between EASL guidelines and American Association for the Study of Liver Diseases (AASLD) guidelines and Asian Pacific Association for the Study of the Liver (APASL) guidelines can be found in Table 1.However, patients with compensated or decompensated cirrhosis and detectable HBV DNA should be considered for treatment, independent of ALT levels. Data from this study demonstrated that the presence of a wild-type virus at baseline was an independent predictor of response to Peg-IFN and can assist in improving patient selection for this treatment option [27]. Moreover, treatment indications should also take into account the patient’s age, health status, family history of HCC or cirrhosis and extrahepatic manifestations.
Lastly, the role of IL28B polymorphisms, clearly indicated as a baseline host factor predictor of response in patients with chronic hepatitis C, has been also investigated in CHB patients. Therefore, further studies are necessary to define the role of IL28B polymorphisms as a baseline factor to improve pretreatment patient selection.A promising approach to improve the cost-effectiveness of Peg-IFN therapy is a response-guided treatment, based on HBsAg kinetics which permit early identification of either responders, for whom continuation of treatment to week 48 could be beneficial, or non-responders who should discontinue IFN treatment. The negative predictive value (NPV) for a sustained response ranged from 82% to 100%, depending on prevalence of HBV genotypes in the various studies.
Overall, therapy with Peg-IFN could be discontinued at week 12 in the 20% of primary non-responders, who are therefore candidates for suppressive therapy with NAs.12.
NA-based therapy: UpdateEntecavir and tenofovir are the third-generation NAs recommended as first line therapy for CHB NA-naive patients by all international guidelines. In registration trials, both antivirals demonstrated a long-lasting efficacy (viral suppression in more than 95% of patients over 5 years) associated with prevention of developing cirrhosis and to a greater extent, with fibrosis regression [36-40]. Moreover, these studies reported a minimal risk of drug resistance (1.2% with ETV after six years and 0% with TDF after 5 years) and a favourable safety profile [39-43]. However, as registration trials are conducted under standardized conditions in well-selected and compliant patients, long-term efficacy and safety of ETV and TDF remain to be confirmed in real-life patients who generally have a more complex clinical profile as they are usually older with a higher prevalence of cirrhosis and comorbidities treated with several concomitant medications.13. Entecavir in real-life practiceCurrently, 2,736 CHB naive patients have been treated with ETV monotherapy in six real-life studies and 4-year efficacy and safety data are available for two of these. In this cohort, at baseline patients were older (median age 58 years), were predominately infected with HBV genotype D (90%), presented a diagnosis of cirrhosis in 49% and concomitant disease in 56%. Viral suppression was achieved in 100% of patients over 48 months of therapy, independent of HBeAg status. Only one patient with a partial virological response at week 48 developed resistance at year 3 of treatment with a cumulative rate of 0.2%.
Only one patient developed resistance, corresponding to a 0.6% cumulative resistance rate up to year-4. The safety profile of ETV in real-life studies has been excellent, as there have been no reports of drug-related adverse reactions, discontinuation, or renal toxicity [44-46].In the VIRGIL multicenter study including 243 consecutive NA-naive patients receiving ETV monotherapy, the cumulative probability of achieving a virological response at week 144 was 90% in HBeAg-positive patients and 99% in HBeAg-negative patients [47].
In this cohort, 81% of patients with partial virological response at 48 weeks reached a virological response during prolonged ETV monotherapy and no patient developed ETV resistance. In addition, data from the Virgil cohort demonstrated that in cirrhotic patients, virological response to ETV is associated with a lower probability of developing a clinical event and disease progression [48]. Tenofovir in real-life practiceA total of 1,203 CHB patients, including both NA-naive and experienced, were treated with TDF monotherapy in real-life.
At baseline, median age was 55 years, 35% of patients had cirrhosis, and concomitant diseases were present in 43% [49].
By month 36, virological response was reached in 86% of HBeAg-positive patients and 98% of HBeAg-negative patients. No patient developed drug resistance and, in HBeAg-positive patients, cumulative probability of HBeAg seroconversion at 30 month was 33%. Most partial virological responders at week 48 achieved undetectable HBV DNA during additional treatment. Data from this European cohort confirmed the safety profile of TDF reported in the registration studies. Discontinuation therapy was reported in 9 patients (3%) including renal-related adverse events in two. The TDF dose was reduced in ten patients (3%) because of a decline in the estimated glomerular filtration rate [49]. Antiviral treatment failureAll patients receiving NA-therapy for CHB should be closely monitored for virologic response defined as undetectable HBV DNA by a sensitive PCR assay. Primary non response seems to be more frequent with Adefovir than with other NAs because of sub-optimal antiviral efficacy. When a primary non response is identified antiviral treatment should be modified to prevent disease progression and drug resistant development. In a compliant patient HBV genotyping for the identification of possible resistant mutations should be performed and a switch to a more potent NA is recommended [7].
Several studies demonstrated that in patients with persisting viremia after 24 weeks of LAM therapy or 48 weeks of ADV therapy, there is a greater risk of resistance development with further treatment, compared to patients with undetectable HBV DNA. Therefore, an alternative treatment should be considered in these patients before emergence of genotypic resistance and a change to a more potent drug (entecavir or tenofovir) without cross-resistance is recommended [7]. With the more potent and high genetic barrier drugs, such as ETV and TDF, it has been shown that the rate of viral suppression continues to increase even after one year of treatment, without evidence of drug-resistance [7].
These data suggest that a modification of therapy is not necessary in patients with partial virological response under entecavir or tenofovir, especially in those with declining serum HBV DNA levels. However, in patients with persisting low viremia or when HBV DNA levels do not continue to decline, treatment should be adapted (switching or adding the other drug) in order to maximize viral suppression and prevent long-term resistance [7]. In compliant patients, virological breakthrough is related to the selection of HBV drug-resistant mutants [50]. Antiviral drug-resistanceAntiviral drug-resistance is defined as the reduced susceptibility of a virus to the inhibitory effect of a drug due to adaptive mutations selected under the selective pressure of antiviral therapy. These amino acid changes reduce the affinity of the enzyme for the antiviral drug, in favor of natural substrates. Moreover, the resistance-associated mutations selected by a particular NA confer at least some degree of cross-resistance to other members of its structural group but may also diminish the sensitivity to NAs from a different chemical group, thus limiting future treatment options (Figure 7).Development of antiviral drug-resistance is a complex and multistep phenomenon.
Figure 8 shows the chronology of events.Initially, during antiviral therapy, there is the emergence of mutants containing the primary mutations which are known to confer resistance to the antiviral drug (genotypic resistance). If treatment is continued, resistant mutants are selected under the selective pressure of the drug, and over time become the dominant viral species, producing the progressive increase in serum HBV DNA levels. The virological breakthrough is then followed by a biochemical breakthrough, defined as elevation in serum alanine aminotransferase, after achieving normalization.
The time span between virological and biochemical breakthrough may vary from weeks to years.Zoulim and Locarnini. The selection of drug-resistant mutants was one of the most important concerns with the first and second generation NAs, especially with LAM (Figure 3).
Currently, the availability of most potent antivirals with a high barrier to resistance, such as entecavir and tenofovir, significantly reduced the rates of resistance.
Consequently, the correct choice of a first-line monotherapy provides the best chance of preventing treatment failure and drug resistance. In clinical practice, the early identification of the virologic breakthrough permits an effective timely rescue therapy, before the biochemical breakthrough, thus avoiding disease progression, decompensation in patients with advanced cirrhosis, and accumulation of secondary mutations which may improve viral fitness and may become the basis for cross-resistance with other NAs.In all patients with a virological breakthrough, genotypic resistance testing should be performed to confirm genotypic resistance and to determine the pattern of mutations. There are two commercially available methods for detection of resistance mutations: a direct PCR-based sequencing, which detects all mutations present in a resistant mutant if it is present in ?20% of the viral quasispecies, and a hybridization-based genotyping method, which can detect only known nucleotide mutations, but is more sensitive, allowing for detection of mutants when they constitute 5% or more of the total viral population. The management of treatment failure has changed significantly in recent years, due to the availability of potent antivirals. An appropriate rescue therapy should be initiated with the most effective antiviral drug without cross-resistance to reduce the risk of selecting multiple drug-resistant viral strains.
The add-on strategy is the therapeutic approach recommended by guidelines, in order to prevent the emergence of multi-drug resistant strains and raise the resistance barrier. However, with the availability of more potent drugs, such as entecavir and tenofovir, there is a trend to recommend a switch to a complementary drug having a high barrier to resistance. The switch strategy does not apply to patients who have been exposed to multiple monotherapies; these patients should be treated with add-on strategies in order to minimize the risk of subsequent treatment failure.



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